HIGHLIGHTS OF PRESCRIBING INFORMATION ------CONTRAINDICATIONS------­ These highlights do not include all the information needed to use None. (4) MOZOBIL safely and effectively. See full prescribing information for MOZOBIL. ------WARNINGS AND PRECAUTIONS------­ . Tumor Cell Mobilization in Leukemia Patients: Mozobil may mobilize MOZOBIL (plerixafor injection), Solution for Subcutaneous use leukemic cells and should not be used in leukemia patients. (5.1) Initial U.S. Approval: 2008 . Hematologic Effects: Increased circulating leukocytes and decreased platelet counts have been obsered. Monitor blood cell counts and ------INDICATIONS AND USAGE------platelet counts durig Mozobil use. (5.2) Mozobil, a hematopoietic stem cel1 mobilizer, is indicated in combination . Potential for Tumor Cell Mobilization: Tumor cells may be released with grulocyte-colony stimulating factor (G-CSF) to mobilize from marrow durig HSC mobilzation with Mozobil and G-CSF. hematopoietic stem cells to the perpheral blood for collection and subsequent Effect of rein fusion of tumor cells is unknown. (5.3) autologous trnsplantation in patients with non-Hodgkin's lymphoma and . Potential for Splenic Rupture: Evaluate patients who report left upper multiple myeloma. (1) abdominal and/or scapular or shoulder pain. (5.4) . Pregnancy: May cause fetal harm. Advise women not to become pregnant ------DOSAGE AND ADMINISTRATION------­ when taking Mozobil. (5.5,8.1) . Initiate Mozobil treatment after the patient has received G-CSF once daily for 4 days. (2.1) ------ADVERSE REACTIONS------­ . Repeat Mozobil dose up to 4 consecutive days. (2.1) Most common adverse reactions (? 10%): diarhea, nausea, fatigue, injection . Select dose based on 0.24 mg/kg actul body weight. (2.1) site reactions, headache, artlgia, diziness, and vomiting. (6) . Administer by subcutaeous injection approximately 1 i hours prior to initiation of apheresis. (2.1) To report SUSPECTED ADVERSE REACTIONS, contact Genzyme . Renal impairment: If creatinine clearnce is ,. 50 mUmin, decrease dose Corporation at 1-877-4MOZOBIL or FDA at 1-800-FDA-I088 or by one-third to 0.1 6 mg/g. (2.3) www.fda.gov/medwatch

------DOSAGE FORMS AND STRENGTHS See 17 for PATIENT COUNSELING INFORMATION . Single-use vial containing 1.2 mL of a 20 mg/mL solution. (3) Revised: 04/2010

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE 8.3 Nursing Mothers 2 DOSAGE AND ADMINISTRATION 8.4 Pediatric Use 2.1 Recommended Dosage and Administration 8.5 Geriatrc Use 2.2 Recommended Concomitat Medications 8.6 Renal Impairent 10 OVERDOSAGE 2.3 Dosing in Renal Impairent 3 DOSAGE FORMS AND STRENGTHS 11 DESCRIPTION 4 CONTRAINDICATIONS 12 CLINICAL PHARMACOLOGY 5 WARINGS AND PRECAUTIONS 12.1 Mechanism of Action 5.1 Tumor Cell Mobilization in Leukemia Patients 12.2 Pharmacodynamics 5.2 Hematologic Effects 12.3 Pharmacokietics 5.3 Potential for Tumor Cell Mobilization 13 NON CLINICAL TOXICOLOGY 5.4 Splenic Enlargement and Potential for Rupture 13.1 Carcinogenesis, Mutagenesis, Impairent of Ferility 5.5 Pregnancy 14 CLINICAL STUDIES 6 ADVERSE REACTIONS 16 HOW SUPPLIED/STORAGE AND HANDLING 6.1 Clinical Trial Experience 17 PATIENT COUNSELING INFORMATION 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS *Sections or subsections omitted from the full prescribing information are not 8.1 Pregnancy listed

Revision Date: January 2009 Proprietary and Confidential Page 1 Mozobil (pleriafor) genze PROPOSED TEXT OF THE LABELING OF THE DRUG

FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE Mozobii(ß (plerixafor injection) is indicated in combination with granulocyte-colony stimulating factor (G-CSF) to mobilize hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in patients with non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM). 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage and Admiistration

Vials should be inspected visually for particulate matter and discoloration prior to administration and should not be used if there is particulate matter or if the solution is discolored.

Begin treatment with Mozobil after the patient has received G-CSF once daily for four days. (see Dosage and Administration (2.2)) Administer Mozobil approximately 11 hours prior to initiation of each apheresis for up to 4 consecutive days.

The recommended dose of Mozobi1 is 0.24 mgig body weight by subcutaneous (SC) injection. Use the patient's actual body weight to calculate the volume of Mozobi1 to be administered. Each vial delivers 1.2 mL of 20 mglmL solution, and the volume to be administered to patients should be calculated from the following equation:

0.012 X patient's actual body weight (in kg) = volume to be administered (in mL)

In clinical studies, Mozobil dose has been calculated based on actual body weight in patients up to 175% of ideal body weight. Mozobi1 dose and treatment of patients weighing more than 175% of ideal body weight have not been investigated.

Based on increasing exposure with increasing body weight, the plerixafor dose should not exceed 40 mglday. (see Clinical Pharmacology (12.3))

2.2 Recommended Concomitant Medications Administer daily morning doses of G-CSF 10 microgramslkg for 4 days prior to the first evening dose of Mozobil and on each day prior to apheresis. (see Clinical Studies (14))

2.3 Dosing in Renal Impairment In patients with moderate and severe renal impairment (estimated creatinine clearance

(CLCR):: 50 mLlmin), reduce the dose of Mozobil by one-third to 0.16 mglkg as shown in Table 1. If CLCR is :: 50 mLimin the dose should not exceed 27 mglday, as the mgig­ based dosage results in increased p1erixafor exposure with increasing body weight. (see Clinical Pharmacology (12.3)) Similar systemic exposure is predicted ifthe dose is reduced by one-third in patients with moderate and severe renal impairment compared with subjects with normal renal fuction. (see Clinical Pharmacology (12.3))

Proprietary and Confidential Page 2 Mozobil (pleriafor) genze PROPOSED TEXT OF THE LABELING OF THE DRUG

T a ble 1: Recommend e dDosaee 0 fPIerixa . i or . in P atients. wit. hRena IImpairment Estimated Creatinine Clearance Dose (mL/min) ~ 50 0.24 mg/kg once daily (not to exceed 40 mg/day) 0( 50 0.16 mg/kg once daily (not to exceed 27 mg/day)

The following (Cockroft-Gault) formula may be used to estimate CLcR:

Males: Creatinine clearance (mL/min) = weight (kg) X (140 - age in years) 72 X serum creatinine (mgldL) Females: Creatinine clearance (mL/min) = 0.85 X value calculated for males

There is insufficient information to make dosage recommendations in patients on hemodial ysis. 3 DOSAGE FORMS AND STRENGTHS Single-use vial containing 1.2 mL of a 20 mglmL solution. 4 CONTRAINDICATIONS None 5 WARNINGS AND PRECAUTIONS 5.1 Tumor Cell Mobilization in Leukemia Patients For the purpose ofHSC mobilization, Mozobil may cause mobilization ofleukemic cells and subsequent contamination of the apheresis product. Therefore, Mozobil is not intended for HSC mobilization and harvest in patients with leukemia.

5.2 Hematologic Effects Leukocytosis

Administration of Mozobil in conjunction with G-CSF increases circulating leukocytes as well as HSC populations. Monitor white blood cell counts during Mozobil use. Exercise clinical judgment when administering Mozobil to patients with peripheral blood neutrophil counts above 50,000/mcL.

Thrombocytopenia Thombocytopenia has been observed in patients receiving Mozobil. Monitor platelet counts in all patients who receive Mozobi1 and then undergo apheresis.

5.3 Potential for Tumor Cell Mobilation When Mozobil is used in combination with G-CSF for HSC mobilization, tumor cells may be released from the marrow and subsequently collected in the leukapheresis product. The effect of potential reinfusion of tumor cells has not been well-studied.

Proprietary and Confidential Page 3 Mozobil (plerixafor) genze PROPOSED TEXT OF THE LABELING OF THE DRUG

5.4 Splenic Enlargement and Potential for Rupture Higher absolute and relative spleen weights associated with extramedullary hematopoiesis were observed following prolonged (2 to 4 weeks) daily plerixafor SC administration in rats at doses approximately 4-fold higher than the recommended human dose based on body surface area. The effect of Mozobil on spleen size in patients was not specifically evaluated in clinical studies. Evaluate individuals receiving Mozobil in combination with G-CSF who report left upper abdominal pain and/or scapular or shoulder pain for splenic integrty.

5.5 Pregnancy Pregnancy Category D Mozobil may cause fetal harm when administered to a pregnant woman. Plerixafor was teratogenic in animals. There are no adequate and well-controlled studies in pregnant women using Mozobil. Women of childbearng potential should be advised to avoid becoming pregnant while receiving treatment with Mozobil. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. (see Use In Specifc Populations (8.1)) 6 ADVERSE REACTIONS 6.1 Clinical Trial Experience The following serious adverse reactions are discussed elsewhere in the labeling:

. Potential for tumor cell mobilization in leukemia patients (see Warnings and Precautions (5.1)) . Increased circulating leukocytes and decreased platelet counts (see Warnings and Precautions (5.2)) . Potential for splenic enlargement (see Warnings and Precautions (5.4))

The most common adverse reactions (2: 10%) reported in patients who received Mozobil in conjunction with G-CSF regardless of causality and more frequent with Mozobil than placebo during HSC mobilization and apheresis were diarrhea, nausea, fatigue, injection site reactions, headache, arthralgia, dizziness, and vomiting.

Safety data for Mozobil in combination with G-CSF were obtained from two randomized placebo-controlled studies (301 patients) and 10 uncontrolled studies (242 patients). Patients were primarily treated with Mozobil at daily doses of 0.24 mgig SC. Median exposure to Mozobil in these studies was 2 days (range 1 to 7 days).

In the two randomized studies in patients with NHL and MM, a total of301 patients were treated in the Mozobil and G-CSF group and 292 patients were treated in the placebo and G-CSF group. Patients received daily morning doses of G-CSF 10 microgramslkg for 4 days prior to the first dose of Mozobil 0.24 mglkg SC or placebo and on each morning prior to apheresis. The adverse reactions that occurred in 2: 5% of the patients who

Proprietary and Confidential Page 4 Mozobil (plerixafor) genze PROPOSED TEXT OF THE LABELING OF THE DRUG

received Mozobil regardless of causality and were more frequent with Mozobil than placebo during HSC mobilization and apheresis are shown in Table 2.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Table 2: Adverse Reactions in:: 5% of Non-Hodgkin's Lymphoma and Multiple Myeloma Patients RecelVln2 M ozo bl i an dore M reQuent F than PI acebo D urin2H SC Mo bT i ization dan Apheresis Percent of Patients (%) Mozobil and G-CSF Placebo and G-CSF (n =301) (n = 292

All Grade 3 Grade 4 All Grade 3 Grade 4 Grades. Grades Gastrointestinal disorders Diarrhea 37 ~ 1 0 17 0 0 Nausea 34 1 0 22 0 0 Vomiting 10 ~ 1 0 6 0 0 Flatulence 7 0 0 3 0 0 General disorders and administration site conditions Iniection site reactions 34 0 0 10 0 0 Fatigue 27 0 0 25 0 0 Musculoskeletal and connective tissue disorders Arhralgia 13 0 0 12 0 0 Nervous svstem disorders Headache 22 ~ 1 0 21 1 0 Dizziness 11 0 0 6 0 0 Psychiatric disorders Insomnia 7 0 0 5 0 0 "Grades based on cntena from the World Health Organization (WHO)

In the randomized studies, 34% of patients with NHL or MM had mild to moderate injection site reactions at the site of subcutaneous administration of Mozobil. These included erythema, hematoma, hemorrhage, induration, inflammation, irrtation, pain,

paresthesia, pruritus, rash, swellng, and urticara.

Mild to moderate systemic reactions were observed in less than 1 % of patients approximately 30 min after Mozobil administration. Events included one or more of the following: urticaria (n = 2), periorbital swelling (n = 2), dyspnea (n = 1) or hypoxia (n = 1). Symptoms generally responded to treatments (e.g., antihistamines, corticosteroids, hydration or supplemental oxygen) or resolved spontaneously.

Vasovagal reactions, orthostatic hypotension, andlor syncope can occur following subcutaneous injections. In Mozobil oncology and healthy volunteer clinical studies, less than 1 % of subjects experienced vasovagal reactions following subcutaneous

Proprietary and Confidential Page 5 Mozobil (pleriafor) genze PROPOSED TEXT OF THE LABELING OF THE DRUG administration ofMozobi1 doses ~ 0.24 mglg. The majority ofthese events occurred within 1 hour of Mozobil administration. Because of the potential for these reactions, appropriate precautions should be taken.

Other adverse reactions in the randomized studies that occurred in 0: 5% of patients but were reported as related to Mozobil during HSC mobilization and apheresis included abdominal pain, hyperhidrosis, abdominal distention, dry mouth, eryhema, stomach discomfort, malaise, hypoesthesia oral, constipation, dyspepsia, and musculoskeletal pam. 7 DRUG INTERACTIONS

Based on in vitro data, p1erixaforis not a substrate, inhibitor or inducer of human cytochrome P450 isozymes. P1erixafor is not likely to be implicated in in vivo drug-drug interactions involving cytochrome P450s. At concentrations similar to what are seen clinically, plerixafor did not act as a substrate or inhibitor ofP-g1ycoprotein in an in vitro study. ¡see Clinical Pharmacology (12.3))

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D Plerixafor was teratogenic in animals. Plerixafor administered to pregnant rats induced embryo-fetal toxicities including fetal death, increased resorptions and post-implantation loss, decreased fetal weights, anophthalmia, shortened digits, cardiac interventricular septal defect, ringed aorta, globular heart, hydrocephaly, dilatation of olfactory ventricles, and retarded skeletal development. Embryo-fetal toxicities occurred mainly at a dose of

90 mg/m2 (approximately 10 times the recommended human dose of 0.24 mg/kg when compared on a mg/m2 basis or 10 times the AUC in subjects with normal renal function who received a single dose of 0.24 mglg). 8.3 Nursing Mothers It is not known whether plerixafor is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from Mozobil, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use The safety and efficacy of Mozobil in pediatric patients have not been established in controlled clinical studies.

8.5 Geriatric Use

Of the total number of subjects in controlled clinical studies ofMozobil, 24% were 65 and over, while 0.8% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Proprietary and Confidential Page 6 Mozobil (plerixafor) gee PROPOSED TEXT OF THE LABELING OF THE DRUG

Since p1erixafor is mainly excreted by the kidney, no dose modifications are necessary in elderly individuals with normal renal function. In general, care should be taken in dose selection for elderly patients due to the greater frequency of decreased renal function with advanced age. Dosage adjustment in elderly patients with CLCR :S 50 mLimin is recommended. (see Dosage and Administration (2.3) and Clinical Pharmacology (12.3))

8.6 Renal Impairment In patients with moderate and severe renal impairment (CLCR :S 50 mLlmin), reduce the dose ofplerixafor by one-third to 0.16 mglg. (see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)) 10 OVERDOSAGE

Based on limited data at doses above the recommended dose of 0.24 mglg SC, the frequency of gastrointestinal disorders, vasovagal reactions, orthostatic hypotension, and/or syncope may be higher. 11 DESCRIPTION

Mozobil (plerixafor injection) is a sterile, preservative-free, clear, colorless to pale yellow, isotonic solution for subcutaneous injection. Each mL of the sterile solution contains 20 mg of plerixafor. Each single-use vial is filled to deliver 1.2 mL of the sterle solution that contains 24 mg ofplerixafor and 5.9 mg of sodium chloride in Water for Injection adjusted to á pH of 6.0 to 7.5 with hydrochloric acid and with sodium hydroxide, if required.

Plerixafor is a hematopoietic stem cell mobilizer with a chemical name l, 1 '-(1 ,4­ pheny1enebis (methylene))-bis-l,4,8,11- tetraazacyc1otetradecane. It has the molecular formula C2gH54Ng. The molecular weight ofplerixafor is 502.79 glmol. The strctural formula is provided in Figure 1. Figure 1: Structural Formula (l (l NH HN Ct) N)ON V J Plerixafor is a white to off-white crystallne solid. It is hygroscopic. P1erixafor has a typical melting point of 131.5 °C. The partition coeffcient of plerixafor between 1­ octano1 and pH 7 aqueous buffer is .. 0.1. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action

Proprietary and Confidential Page 7 Mozobil (plerixafor) gee PROPOSED TEXT OF THE LABELING OF THE DRUG

Plerixafor is an inhibitor of the CXCR4 chemokine receptor and blocks binding of its cognate ligand, stromal cell-derived factor-lq (SDF-1a). SDF-la and CXCR4 are recognized to playa role in the trafficking and homing of human hematopoietic stem cells (HSCs) to the marrow comparment. Once in the marrow, stem cell CXCR4 can act to help anchor these cells to the marrow matrix, either directly via SDF-1a or through the induction of other adhesion molecules. Treatment with p1erixafor resulted in leukocytosis and elevations in circulating hematopoietic progenitor cells in mice, dogs and humans. CD34+ cells mobilized by plerixafor were capable of engraftment with long-term repopulating capacity up to one year in canine transplantation models.

12.2 Pharmacodynamics Data on the fold increase in peripheral blood CD34+ cell count (cells/mcL) by apheresis day were evaluated in two placebo-controlled clinical studies in patients with NHL and MM (Study 1 and Study 2, respectively). The fold increase in CD34+ cell count (cells/mcL) over the 24-hour period starting from the day prior to the first apheresis and ending the next mOffingjust before the first apheresis is summarized in Table 3. During this 24-hour period, a single dose of Mozobil or placebo was administered 10 to 11 hours prior to apheresis.

Table 3: Fold Increase in Peripheral Blood CD34+ Cell Count Following Pretreatment with G-CSF and Administration of Plerixafor Mozobil and G-CSF Placebo and G-CSF Study

Median Mean (SD) Median Mean (SD) Study 1 5.0 6.1 (5.4) 1.4 1.9 (1.5) Study 2 4.8 6.4 (6.8) 1.7 2.4(7.3)

In pharmacodynamic studies of Mozobi1 in healthy volunteers, peak mobilization of CD34+ cells was observed between 6 and 9 hours after administration. In pharmacodynamic studies ofMozobil in conjunction with G-CSF in healthy volunteers, a sustained elevation in the peripheral blood CD34+ count was obsered from 4 to 18 hours after plerixafor administration with a peak CD34+ count between 10 and 14 hours.

12.3 Pharmacokinetics

The single-dose pharmacokinetics of plerixafor 0.24 mgig were evaluated in patients with NHL and MM following pre-treatment with G-CSF (10 microgramslkg once daily for 4 consecutive days). Plerixafor exhibits linear kinetics between the 0.04 mgig to 0.24 mgig dose range. The pharmacokinetics of plerixafor were similar across clinical studies in healthy subjects who received plerixafor alone and NHL and MM patients who received p1erixafor in combination with G-CSF.

A population pharmacokinetic analysis incorporated plerixafor data from 63 subjects (NHL patients, MM patients, subjects with varying degrees of renal impairment, and healthy subjects) who received a single SC dose (0.04 mgig to 0.24 mgig) of

Proprietary and Confidential Page 8 Mozobil (plerixafor) genze PROPOSED TEXT OF THE LABELING OF THE DRUG plerixafor. A two-compartment disposition model with first order absorption and elimination was found to adequately describe the plerixafor concentration-time profile. Significant relationships between clearance and creatinine clearance (CLCR), as well as between central volume of distrbution and body weight were observed. The distribution half-life (tl/Za) was estimated to be 0.3 hours and the terminal population half-life (tl/zß) was 5.3 hours in patients with normal renal function.

The population pharmacokinetic analysis showed that the mglg-based dosage results in an increased plerixafor exposure (AUCO-Z4h) with increasing body weight. There is limited experience with the 0.24 mglkg dose of pi erixa for in patients weighing above 160 kg. Therefore the dose should not exceed that of a 160 kg patient (i.e., 40 mglday if CLCR is :: 50 mLimin and 27 mglday if CLCR is ~ 50 mLlmin). (see Dosage and Administration (2.1, 2.3))

Absorption Peak plasma concentrations occurred at approximately 30 - 60 minutes after a SC dose.

Distribution Plerixafor is bound to human plasma proteins up to 58%. The apparent volume of distrbution of plerixafor in humans is 0.3 Llkg demonstrating that p1erixafor is largely confined to, but not limited to, the extravascular fluid space.

Metabolism The metabolism of plerixafor was evaluated with in vitro assays. P1erixafor is not metabolized as shown in assays using human liver microsomes or human primary hepatocytes and does not exhibit inhibitory activity in vitro towards the major drug metabolizing cytochrome P450 enzymes (IA2, 2C9, 2C19, 2D6, and 3A4/5). In in vitro studies with human hepatocytes, plerixafor does not induce CYP1A2, CYP2B6, or CYP3A4 enzymes. These findings suggest that plerixafor has a low potential for involvement in cytochrome P450-dependent drug-drug interactions. Elimination The major route of elimination of p1erixafor is urinary. Following a 0.24 mglg dose in healthy volunteers with normal renal function, approximately 70% ofthe dose was excreted in the urine as the parent drug during the first 24 hours following administration. In studies with healthy subjects and patients, the terminal half-life in plasma ranges between 3 and 5 hours. At concentrations similar to what are seen clinically, p1erixafor did not act as a substrate or inhibitor ofP-g1ycoprotein in an in vitro study with MDCKII and MDCKII-MDRI cell models.

Renal Impairment Following a single 0.24 mglkg SC dose, plerixafor clearance was reduced in subjects with varying degrees of renal impairment and was positively correlated with CLCR. The mean AUCO-Z4h ofplerixafor in subjects with mild (CLCR 51-80 mLlmin), moderate (CLCR 31-50 mLlmin), and severe (CLCR ~ 31 mLimin) renal impairment was 7%, 32%, and 39% higher than healthy subjects with normal renal function, respectively. Renal

Proprietary and Confidential Page 9 Mozobil (plerixafor) genze PROPOSED TEXT OF THE LABELING OF THE DRUG

impairment had no effect on Cmax. A population pharacokinetic analysis indicated an increased exposure (AUCO-24h) in patients with moderate and severe renal impairment compared to patients with CLCR :; 50 mLimin. These results support a dose reduction of one-third in patients with moderate to severe renal impairment (CLCR ~ 50 mLimin) in order to match the exposure in patients with normal renal function. The population pharmacokinetic analysis showed that the mg/kg-based dosage results in an increased plerixafor exposure (AUCO-24h) with increasing body weight; therefore ifCLcR is ~ 50 mLimin the dose should not exceed 27 mglday. (see Dosage and Administration (2.3))

Since p1erixafor is primarily eliminated by the kidneys, coadministration of p1erixafor with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of p1erixafor or the coadministered drug. The effects of coadministration of p1erixafor with other drugs that are renally eliminated or are known to affect renal function have not been evaluated.

Race Clinical data show similar plerixafor pharmacokinetics for Caucasians and Afrcan- Americans, and the effect of other raciallethnic groups has not been studied. Gender Clinical data show no effect of gender on plerixafor pharmacokinetics. Age Clinical data show no effect of age on p1erixafor pharacokinetics.

12.4 QT/QTc Prolongation

There is no indication of a QT/QTc prolonging effect of Mozobil in single doses up to 0.40 mglg. In a randomized, double-blind, crossover study, 48 healthy subjects were administered a single subcutaneous dose of Mozobi1 (0.24 mglg and 0.40 mglg) and placebo. Peak concentrations for 0.40 mglg Mozobil were approximately 1.8-fo1d higher than the peak concentrations following the 0.24 mglg single subcutaneous dose.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertilty Carcinogenicity studies with plerixafor have not been conducted.

Plerixafor was not genotoxic in an in vitro bacterial mutation assay (Ames test in Salmonella), an in vitro chromosomal aberration test using V79 Chinese hamster cells, or an in vivo bone marrow micronucleus test in rats after subcutaneous doses up to 25 mglg (150 mg/m2).

The effect of plerixafor on human fertility is unkown. The effect of p1erixafor on male or female fertility was not studied in designated reproductive toxicology studies. The

Proprietary and Confidential Page 10 Mozobil (plerixafor) gee PROPOSED TEXT OF THE LABELING OF THE DRUG

staging of spermatogenesis measured in a 28-day repeated dose toxicity study in rats revealed no abnormalities considered to be related to p1erixafor. No histopathological

evidence of toxicity to male or female reproductive organs was observed in 28-day repeated dose toxicity studies.

14 CLINICAL STUDIES

The efficacy and safety of Mozobil in conjunction with G-CSF in non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM) were evaluated in two placebo-controlled studies (Studies 1 and 2). Patients were randomized to receive either Mozobi1 0.24 mgig or placebo on each evening prior to apheresis. Patients received daily morning doses ofG-CSF 10 micrograms/kg for 4 days prior to the first dose ofMozobil or placebo and on each morning prior to apheresis. Two hundred and ninety-eight (298) NHL patients were included in the primary effcacy analyses for Study 1. The mean age was 55.1 years (range 29-75) and 57.5 years (range 22-75) in the Mozobi1 and placebo groups, respectively, and 93% of subjects were Caucasian. Thee hundred and two (302) MM patients were included in the primary efficacy analyses for Study 2. The mean age was 58.2 years (range 28-75) and 58.5 years (range 28-75) in the Mozobi1 and placebo groups, respectively, and 81 % of sùbjects were Caucasian.

In Study 1, 59% ofNHL patients who were mobilized with Mozobil and G-CSF collected 2: 5 X 106 CD34+ cells/kg from the peripheral blood in four or fewer apheresis sessions, compared with 20% of patients who were mobilized with placebo and G-CSF (p .. 0.001). Other CD34+ cell mobilization outcomes showed similar findings (Table 4).

Table 4: Study 1 Effcacy Results - CD34+ Cell Mobilization in NHL Patients Mozobil and Placebo Effcacy Endpoint G-CSF and G-CSF p-valuea (n = 150) (n = 148) Patients achieving 2: 5 X 106 cells/kg in :: 4 apheresis days 89 (59%) 29 (20%) .. 0.001 Patients achieving 2: 2 X 106 cells/kg in:: 4 apheresis days 130 (87%) 70 (47%) .. 0.001 'p-value calculated using Pearson's Chi-Squared test

The median number of days to reach 2: 5 x 106 CD34+ cells/kg was 3 days for the Mozobil group and not evaluable for the placebo group. Table 5 presents the proportion of patients who achieved 2: 5 x 106 CD34+ cells/kg by apheresis day.

Table 5: Study 1 Effcacy Results - Proportion of Patients Who Achieved 2: 5x 106 CD34+ ce s ii(2 /k)Y ~pJbAh eresis . D av. NHLII Patients . Proportona Proportiona Days in Mozobil and G-CSF in Placebo and G-CSF (n=147b) (n=142b) 1 27.9% 4.2% 2 49.1% 14.2% 3 57.7% 21.6%

Proprietary and Confidential Page 11 Mozobil (plerixafor) gee PROPOSED TEXT OF THE LABELING OF THE DRUG

Iapercents 4 determed I by Kaplan65.6% Meier method 24.2% b n includes all patients who received at least one day of apheresis

In Study 2, 72% ofMM patients who were mobilized with Mozobil and G-CSF collected 2: 6 X 106 CD34+ cells/kg from the peripheral blood in two or fewer apheresis sessions, compared with 34% of patients who were mobilzed with placebo and G-CSF (p -: 0.001). Other CD34+ cell mobilization outcomes showed similar findings (Table 6).

Table 6: Study 2 Effcacy Results - CD34+ Cell Mobilzation in Multiple Myeloma Patients Mozobil and Placebo and Effcacy Endpoint G-CSF G-CSF p-valuea (n = 148) (n = 154) Patients achieving 2: 6 X 106 cells/kg in ~ 2 apheresis days 106 (72%) 53 (34%) -: 0.001 Patients achieving 2: 6 X 106 cells/kg in ~ 4 apheresis days 112 (76%) 79 (51 %) -: 0.001 Patients achieving 2: 2 X 106 cells/kg in ~ 4 apheresis days 141 (95%) 136 (88%) 0.028 'p-value calculated using Pearson's Chi-Squared test

The median number of days to reach 2: 6 x 106 CD34+ cells/kg was 1 day for the Mozobil group and 4 days for the placebo group. Table 7 presents the proportion of patients who achieved 2: 6 x 106 CD34+ cells/kg by apheresis day.

Table 7: Study 2 - Proportion of Patients Who Achieved 2: 6 x 106 CD34+ ceIIs ke: / by A iPt h eresis . Dayin . MMP atients. Proportiona Proportona Days in Mozobil and G-CSF in Placebo and G-CSF (n=144") (n=150b) 1 54.2% 17.3% 2 77.9% 35.3% 3 86.8% 48.9% 4 86.8% 55.9% 'Percents determned by Kaplan Meier method b n includes all patients who received at least one day of apheresis

Multiple factors can influence time to engraftment and graft durability following stem cell transplantation. For transplanted patients in the Phase 3 studies, time to neutrophil and platelet engraftment and graft durability were similar across the treatment groups.

16 HOW SUPPLIED/STORAGE AND HANDLING Each single-use vial is filled to deliver 1.2 mL of 20 mglmL solution containing 24 mg of p1erixafor.

NDC Number: 58468-0140-1

Proprietary and Confidential Page 12 Mozobil (pleriafor) genze PROPOSED TEXT OF THE LABELING OF THE DRUG

. Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). (see USP Controlled Room temperature) . Each vial of Mozobil is intended for single use only. Any unused drug remaining after injection must be discarded.

17 PATIENT COUNSELING INFORMATION Advise patients of the signs and symptoms of potential systemic reactions such as urticaria, periorbital swelling, dyspnea, or hypoxia during and following Mozobil injection. ¡see Adverse Reactions (6.1))

Patients should inform a health care professional immediately if symptoms of vasovagal reactions such as orthostatic hypotension or syncope occur during or shortly after thèir

Mozobil injection. ¡see Adverse Reactions (6.1))

If patients experience itching, rash, or reaction at the site of injection, they should notify a health care professional as these symptoms have been treated with over-the-counter medications during clinical trials. ¡see Adverse Reactions (6.1))

Inform patients that Mozobi1 may cause gastrointestinal disorders, including diarrhea, nausea, vomiting, flatulence, and abdominal pain. Patients should be told how to manage specific gastrointestinal disorders and to inform their health care professional if severe events occur following Mozobi1 injection. ¡see Adverse Reactions (6.1))

Advise female patients with reproductive potential to use effective contraceptive methods during Mozobil use. ¡see Warnings and Precautions (5.5) and Use In Specifc Populations (8.1))

Manufactured by: Patheon UK Ltd., Swindon, UK Manufactured for: Genzyme Corporation, 500 Kendall Street, Cambridge, MA 02142 USA tÇ2010 Genzyme Corporation. All rights reserved. Mozobi1 is a registered trademark of Genzyme Corporation.

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